Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen

S J Duthie, W T Melvin, M D Burke

    Research output: Contribution to journalArticle

    20 Citations (Scopus)

    Abstract

    1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.
    Original languageEnglish
    Pages (from-to)1151-64
    Number of pages14
    JournalXenobiotica
    Volume25
    Issue number10
    Publication statusPublished - 1995

    Fingerprint

    Hep G2 Cells
    Tamoxifen
    Drug-Related Side Effects and Adverse Reactions
    Cyclosporine
    Toxicity
    Hepatocellular Carcinoma
    Pharmaceutical Preparations
    Glutathione
    Metyrapone
    Ketoconazole
    alpha-Tocopherol
    Cell death
    Cytochromes c
    Malondialdehyde
    Superoxides
    Cytochrome P-450 Enzyme System
    Lipid Peroxidation
    Superoxide Dismutase
    Cysteine
    Cell Survival

    Keywords

    • Animals
    • Antineoplastic Agents, Hormonal
    • Biotransformation
    • Carcinogens
    • Cell Survival
    • Cyclosporine
    • Cytochrome P-450 Enzyme System
    • Glutathione
    • Humans
    • Lipid Peroxides
    • Liver Neoplasms, Experimental
    • Malondialdehyde
    • Tamoxifen
    • Tumor Cells, Cultured
    • Vitamin E

    Cite this

    Duthie, S. J., Melvin, W. T., & Burke, M. D. (1995). Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen. Xenobiotica, 25(10), 1151-64.

    Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen. / Duthie, S J; Melvin, W T; Burke, M D.

    In: Xenobiotica, Vol. 25, No. 10, 1995, p. 1151-64.

    Research output: Contribution to journalArticle

    Duthie, SJ, Melvin, WT & Burke, MD 1995, 'Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen', Xenobiotica, vol. 25, no. 10, pp. 1151-64.
    Duthie, S J ; Melvin, W T ; Burke, M D. / Drug toxicity mechanisms in human hepatoma HepG2 cells: cyclosporin A and tamoxifen. In: Xenobiotica. 1995 ; Vol. 25, No. 10. pp. 1151-64.
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    N2 - 1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.

    AB - 1. Mechanisms of drug toxicity operating in human HepG2 hepatoma cells have been assessed using cyclosporin A (CsA) and tamoxifen as examples. 2. Either 150 microM CsA or 50 microM tamoxifen caused approximately 50% loss of HepG2 cell viability. alpha-Tocopherol (32 microM) almost completely prevented cell death due to either CsA or tamoxifen. Tamoxifen stimulated malondialdehyde formation. The toxicity of CsA but not tamoxifen was increased by the glutathione synthesis inhibitor, buthionine-S,R-sulphoximine, and decreased by the glutathione precursor, L-cysteine. Thus, while both CsA and tamoxifen toxicities involved lipid peroxidation, reduced glutathione (or sulphydryl groups) protected against CsA but not tamoxifen. 3. CsA was metabolized to M1 and/or M17 in HepG2 cells. The effects of the cytochrome P450 inhibitors, ketoconazole and metyrapone, indicated that P450 played a role in the toxicity of CsA but not tamoxifen. The effects of superoxide dismutase and cytochrome c indicated that tamoxifen toxicity involved superoxide formation. 4. These results show that several oxidative mechanisms of drug toxicity operate in HepG2 cells.

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